A RECIRCULATORY PHARMACOKINETIC MODEL DESCRIBING THE CIRCULATORY MIXING, TISSUE DISTRIBUTION AND ELIMINATION OF ANTIPYRINE IN DOGS

A model of antipyrine disposition from the moment of its injection was developed incorporating the intravascular mixing component as determi ned by indocyanine green (ICG) kinetics. The simultaneous dispositions of antipyrine and ICG were characterized in five dogs anesthetized wi th halothane. After injecting antipyrine and ICG into the right atrium , femoral arterial blood samples were collected every 3 sec for the 1 st min and less frequently to 20 min for ICG and to 360 min for antipy rine. ICG and antipyrine concentrations were measured by high-performa nce liquid chromatography and modeled with SAAM 30.1. A fully identifi able recirculatory compartmental model, incorporating the ICG recircul atory model with blood flows and time delays, was used to describe ant ipyrine disposition. Four distinct antipyrine pharmacokinetic tissue c ompartments and the distribution clearances assigned to them could be estimated: a pulmonary tissue (0.13 +/- 0.05 I, and 2.51 +/- 0.39 lite rs/min), a very fast equilibrating tissue (0.12 +/- 0.08 I, and 1.33 /- 0.22 liters/min), a fast equilibrating tissue (3.21 +/- 0.45 I, and 0.74 +/- 0.09 liters/min) and a slow equilibrating tissue (15.94 +/- 1.8 I, and 0.44 +/- 0.13 liters/min). Although this recirculatory mode l retains the predominant attributes of traditional pharmacokinetic mo dels, it also can describe completely drug concentrations during the m ixing transient when many drugs reach peak effect as well as ascertain the role of cardiac output and its distribution in drug disposition.